Aortic aneurysms account for 1-2% of all deaths in industrialized countries. Marfan syndrome (MSF) is a common genetic disease that represents the most well studied situation for understanding the pathogenesis of aortic aneurysms. Currently, there are no proven drugs preventing aneurysm progression, dissection and rupture. Therefore, there is a pressing need to develop effective therapies. A better understanding of the pathogenesis of aortic aneurysms should provide new targets for developing treatments to aneurysms. Marfan syndrome is caused by FBN1 protein mutations that activate TGF? signaling to drive aneurysm formation. Using a Marfan mouse model that harbors the FBN1C1039G mutation found in Marfan patients, losartan was discovered to prevent aneurysm formation. Distinct from the well-established TGF? signaling paradigm, recent discoveries of mutations in smooth muscle cell (SMC) actin cytoskeleton proteins such as SM ?actin (ACTA2) and ?-myosin (MYH11) in patients with thoracic aortic aneurysm and dissection highlight a new mechanism of actin cytoskeleton contractile dysfunction in the pathogenesis of aneurysms. SM22, an actin binding protein, is known to significantly downregulated in the aneurysms of Marfan patients. Our published studies demonstrate that SM22 deficiency disrupts actin cytoskeleton and promotes oxidative stress and vascular inflammation upon vascular injury. Recently, a series of studies show that SM22 is a multifunctional protein that regulates VSMC phenotypic modulation via activating Erk1/2, and Oxidative stress-mediated NF-kB pathways. Here we propose to explore the role of SM22 in the pathogenesis of aneurysms. Our preliminary results show that deletion of Sm22 in the Fbn1C1039G/+ Marfan mouse background exacerbates aneurysm formation and rupture. The goal of this proposal is to determine the molecular mechanisms of SM22 in the pathogenesis of aneurysm formation in a new Marfan mouse model. We hypothesize that SM22 deficiency with defective FBN1 aggravates aneurysm formation and rupture by stimulating the crosstalk of both the established TGF?Erk1/2 signaling pathways and the actin cytoskeleton contractile dysfunction-induced oxidative stress and inflammation signaling pathways. Aim 1: we will systematically characterize the pathogenesis of aneurysm formation and rupture in our Sm22-/-Fbn1C1039G/+ mice in vivo; Aim 2: we will determine the molecular mechanisms of SM22 deficiency on TGF?Erk1/2, oxidative stress and NF-kB pathway activation in FBN1 defective VSMCs using well established molecular, cellular and bioinformatics approaches. Successful completion of this research will shed light on the pathogenesis of aneurysm formation and rupture. SM22 may represent a target for new therapies for aortic aneurysms. Importantly, this study will provide validation for a new mouse aneurysm model that mimics closely human aneurysm formation and rupture.